Hepatoid adenocarcinoma (HAC) is a rare α-fetoprotein (AFP)-producing tumor, which has a poor prognosis and ineffective treatment options. HAC consists of eosinophilic cytoplasm and centrally located nuclei that closely resembling the hepatocellular carcinoma (HCC) cells. The primary sites of origin for HAC are lungs, with an occurrence rate of 5% among lung cancer cases. Despite that conventional lung cancer treatments have been proven ineffective for treating hepatoid adenocarcinoma of lung (HAL), early diagnosis and aggressive treatment can result in long-term survival. Since patients with HAL seldom exhibit specific clinical manifestations, an accurate and timely diagnosis is challenging. Hence, the pathological characteristics of HAL may be crucial for its early diagnosis. In this study, we present a case of an old male patient with primary HAL.
2 Case report
We report a 70-year-old Chinese male patient with alcoholic intake over 30 years and smoking history of 60 cigarettes per day for 40 years. He sought medical consultation for productive cough and hemoptysis sputum. Chest CT scan revealed a mass (6.4 × 5.5 cm) in the left lower lobe of the lung. Mediastinal lymph nodes of the patient were slightly swollen (Fig. 1). An abdominal CT scan demonstrated that no definite focal lesion was observed in the liver, spleen, pancreas and gall bladder. Brain magnetic imaging revealed the occurrence of multiple small lacunes in the brain. No abnormal enhanced masses or nodules was found in the bilateral cerebral hemispheres, pons and cerebellum. Respiratory system tumor marker tests indicated that the levels of carcinoembryonic antigen (CEA) and CK19 were increased to 11.16 ng/ml and 7.01 ng/ml, respectively. It was noted that the total number of red blood cells (3.93 × 10↓) and the biochemical levels of ALT (54 U/L↑), AST (87 U/L↑) and γ-GT (990 U/L↑) were abnormal. These abnormalities may be due to chronic excessive alcohol consumption.
The patient underwent curative surgical resection on August 4, 2014. During thoracoscopic examination, an 8 × 5 cm mass was found in the left lower lobe of the lung, with adhesion to visceral pleura (Fig. 2). Moreover, the tumor was spread to a small part of the left upper lobe. Therefore, a left pneumonectomy with radical lymph node dissection was performed. Macroscopic examination revealed that the tumor (6 × 6 × 5.5 cm) measured on the largest cut surface appeared as a solid gray-white node. Furthermore, visceral pleural invasion was observed in this patient.
Hematoxylin and eosin staining indicated a poorly differentiated carcinoma arranged in a sheet-like or trabecular growth pattern, with occasional tubular regions (Fig. 3). Extensive necrosis was noted in this patient. The tumor cells were large and polygonal, with abundant eosinophilic cytoplasm and centrally-located prominent nucleoli. Cytoplasmic bile plugs and periodic acid-Schiff-positive, diastase-resistant hyaline globules were found in this patient (Fig. 3). These morphological features were relatively similar to HCC. In addition, this case exhibited high mitotic counts (30–40 mitotic figures per 2 mm2) and high proliferation index (Ki67 scores: 30%).
Immunohistochemical (IHC) analysis revealed that the neoplastic cells were strongly positive for HepoPar-1, CKpan, CK8/18, CK19 and MOC31 (anti-EpCAM), while focally positive for AFP and monoclonal CEA. CD34 staining demonstrated an intricate network of sinusoidal vessels surrounded the tumor cells. In contrast, Arg-1, SALL-4, CK5/6, CK7, CK14, CK20, syn, CD56, TTF-1, napsin A, P40, P63, P53, EGFR and ALK staining were considered negative were found to be negative by IHC staining (Fig. 3). Besides, the hilar lymph node was invaded (1/2). Taking into consideration the clinical, morphological and immunohistochemical features, this patient was diagnosed as HAL. Of note, his pathological staging was pT3N1M0.
Serum level of AFP was not measured prior to surgical operation. On the tenth postoperative day, the serum AFP level was detected as normal (2.07 IU/ml). This patient discharged on the twentieth day and refused further chemotherapy. Eighteen months after primary diagnosis, this patient died of multiple organ failure caused by distant metastases.
HAC was first recognized as a gastric tumor in 1985 by Ishikura et al, as defined by having an extremely high serum level of AFP and morphological features similar to HCC. This rare tumor can be found as a primary carcinoma in extrahepatic organs such as lung, ovary, pancreas, urinary bladder, ampulla of Vater, endometrium and uterine cervix. The most common site of HAC is gastric (63%), followed by ovaries (10%), lung (5%), gallbladder (4%), pancreas (4%) and uterus (4%).
HAL was first described by Ishikura et al in 1990. They studied 7 cases of AFP-producing lung carcinoma and diagnosed 5 of the 7 cases with HAC. Two criteria have been adopted by them for the diagnosis of HAL:
- typical acinar or papillary adenocarcinoma; and
- a component of carcinoma that resembles HCC and produces AFP.
However, later reports described HAL as a component of neuroendocrine carcinoma or signet-ring cells, instead of adenocarcinoma.[11,12] In patients without high AFP level, both morphology and immunophenotyping can assist the diagnosis of HAL.[13–16] In 2014, Haninger et al have modified the Ishikura diagnostic criteria for HAL:
- the tumor can be pure HAC or has a component of typical acinar or papillary adenocarcinoma, signet-ring cells or neuroendocrine carcinoma; and
- AFP expression is not mandatory for diagnosis as long as other markers of hepatic differentiation are expressed.
The morphological features of HAL are remarkably similar to HCC. Since lung is the most common site for extrahepatic metastasis, the omission of metastatic HCC is clinically relevant. Computed tomography (CT) examination and immunostaining patterns may be particularly useful in this regard. CT can be used to detect the location of HAL tumor. However, if there are multiple tumors in different locations, it can be difficult to identify the primary tumor site. Haninger et al have used a panel of antibodies to detect the immunohistochemical profiles of five patients with HAL and HCC. They found that all of them co-expressed APF, HepPar 1, CK8 and CK18, and exhibited positive cytoplasmic staining for TTF-1, but not CK14. Unlike HCC, HAL patients expressed only napsin A, monoclonal CEA, EpCAM markers of HEA125 and MOC31, and a variety of cytokeratins such as CK5/6, CK7, CK19 and CK20. On the contrary, the panel of cytokeratins, napsin A and EpCAM markers are not expressed in HCC patients. Immunostaining reveal that the co-localization of CEA to the cytoplasm and cell membrane is found in 3 out of 5 HAL cases. Nevertheless, HCC is not stained by monoclonal CEA, but demonstrates a distinctive canalicular staining pattern with polyclonal CEA.
A systematic search in PUBMED was conducted to identify all HAC cases reported in the English literature prior to Dec 2016. The search was carried out using the search terms of “AFP producing tumor lung”, “hepatoid carcinoma lung” and “hepatoid adenocarcinoma lung”. The results of literature search and article selection were reviewed and verified by all authors in order to ensure data accuracy and appropriateness. After reviewing the literature, all cases with primary pulmonary hepatoid carcinoma are listed in Table 1.[11,44] A dramatic male predominance of 37/41 cases (90%) was found in this disease, and all of them, except one, were heavy smokers. Patients included in this study had a mean age of 60.5 years (range, 36–82 years). There is no characteristic imaging features of HAL. But in general, a chest radiograph and chest CT revealed a mass in the lung. It is probably that the mass shows heterogeneous enhancement on contrast chest CT images and intense FDG uptake on PET/CT images. The size of tumor was ranged from 1 to 20 cm in the largest dimension, with a mean size of 6.8 cm. Most cases (89%) were detected with a tumor size of greater than 3 cm, which located at the right upper lobe (44%). The majority of patients suffered from advanced stage disease and poor prognosis. In addition, metastases of the rib, vertebra, adrenal, brain, liver and tonsil were reported among HAL patients. Only few patients demonstrated long term disease-free survival, including a female patient with stage IV disease who is alive 9 years after diagnosis. These findings suggest that the clinical stage is the most significant prognostic factor for HAL, as similar to other types of non-small cell lung cancer. Pretreatment levels of AFP were markedly elevated in 22 out of the 26 detected patients. According to the modified diagnostic criteria of HAL, AFP expression is not mandatory for HAL diagnosis, provided that other markers of hepatic differentiation are expressed. However, an elevated serum AFP levels may indicate an increased risk of HAC among elderly male smokers with lung mass.
HAL is an extremely heterogeneous type of tumor, and thus no standard treatment is available at present. The common regimens for HAL patients are: surgical resection, chemotherapy and radiotherapy. A comprehensive review of all published cases has suggested that HAL patients diagnosed at early stage were associated with longer survival time after surgical treatment. For advanced stage patients, efforts continue in attempting radiotherapy and chemotherapy regimens. Gavarancic et al have reported that a combination of sorafenib and platinum-based doublet chemotherapy is well-tolerated in AFP-producing, EGFR wild-type HAL patient. As a result, the patient with stage IV unresectable HAL demonstrated a long-term survival benefit after the proposed treatment. Additionally, Valle et al have described a 30 Gray (Gy) irradiation to achieve durable tumor control in HAL patients through intensity-modulated radiation therapy (IMRT). Such treatment has been proven effective for palliation of symptoms arising from metastatic HAL.
Nonetheless, this study had several weaknesses, primarily the small sample size due to the rarity of HAL. Therefore, more cases should be concerned and recruited. Despite this limitation, we presented a new case of HAL and comprehensively summarized his clinical features, modified diagnostic criteria and treatments of the previously reported cases, in order to provide clinicians and pathologists with a more complete understanding of this rare tumor for avoiding misdiagnosis and mistreatment.
In summary, HAL is a rare tumor with male predilection and morphologically resembles metastatic HCC. Distinguishing it from metastatic HCC may require radiologic-morphologic-immunophenotypic correlation. AFP expression is not a requisite for the clinical diagnosis of HAL, but elevated AFP serum levels may indicate an increased risk of HAC among elderly male smokers with lung mass. Surgical resection appears to be the most effective treatment option for early stage HAL patients, which relies heavily on the histological diagnosis. Certain types of chemotherapy and radiotherapy can be effective in treating HAL. Further studies are needed to develop new treatments for this rare disease.
Data curation: Kun Yang, Qiuyao Li.
Methodology: Qiuyao Li.
Writing – original draft: Kun Yang, Qiuyao Li, Huifeng Jiang.
Writing – review & editing: Kun Yang, Qiuyao Li.
Qiuyao Li orcid: 0000-0001-7681-2580.
. Adachi Y, Tsuchihashi J, Shiraishi N, et al. AFP-producing gastric carcinoma: multivariate analysis of prognostic factors in 270 patients. Oncology 2003;65:95–101.
. Metzgeroth G, Ströbel P, Baumbusch T, et al. Hepatoid adenocarcinoma
- review of the literature illustrated by a rare case originating in the peritoneal cavity. Onkologie 2010;33:263–9.
. Ishikura H, Fukasawa Y, Ogasawara K, et al. An AFP-producing gastric carcinoma with features of hepatic differentiation. A case report. Cancer 1985;56:840–8.
. Ishikura H, Scully RE. Hepatoid carcinoma of the ovary. A newly described tumor. Cancer 1987;60:2775–84.
. Paner GP, Thompson KS, Reyes CV. Hepatoid carcinoma of the pancreas. Cancer 2000;88:1582–9.
. Sinard J, Macleay L Jr, Melamed J. Hepatoid adenocarcinoma
in the urinary bladder. Unusual localization of a newly recognized tumor type. Cancer 1994;73:1919–25.
. Gardiner GW, Lajoie G, Keith R. Hepatoid adenocarcinoma
of the papilla of Vater. Histopathology 1992;20:541–4.
. Hoshida Y, Nagakawa T, Mano S, et al. Hepatoid adenocarcinoma
of the endometrium associated with alpha-fetoprotein production. Int J Gynecol Pathol 1996;15:266–9.
. Kato K, Suzuka K, Osaki T, et al. Primary hepatoid adenocarcinoma
of the uterine cervix. Int J Gynecol Cancer 2007;17:1150–4.
. Ishikura H, Kanda M, Ito M, et al. Hepatoid adenocarcinoma
: a distinctive histological subtype of alpha-fetoprotein-producing lung
carcinoma. Virchows Arch A Pathol Anat Histopathol 1990;417:73–80.
. Hiroshima K, Iyoda A, Toyozaki T, et al. Alpha-fetoprotein-producing lung
carcinoma: report of three cases. Pathol Int 2002;52:46–53.
. Kishimoto T, Yano T, Hiroshima K, et al. A case of alpha-fetoprotein-producing pulmonary carcinoma with restricted expression of hepatocyte nuclear factor-4* in hepatoid foci: a case report with studies of previous cases. Hum Pathol 2008;39:1115–20.
. Wu Z, Upadhyaya M, Zhu H, et al. Hepatoid adenocarcinoma
: computed tomographic imaging findings with histopathologic correlation in 6 cases. J Comput Assist Tomogr 2007;31:846–52.
. Fornasa F. Soft-tissue localization of hepatoid adenocarcinoma
: first case report. Case Rep Oncol 2010;3:212–7.
. Khozin S, Roth MJ, Rajan A, et al. Hepatoid carcinoma of the lung
with anaplastic lymphoma kinase gene rearrangement. J Thorac Oncol 2012;7:e29–31.
. Grossman K, Beasley MB, Braman SS. Hepatoid adenocarcinoma
of the lung
: review of a rare form of lung
cancer. Respir Med 2016;119:175–9.
. Haninger DM, Kloecker GH, Bousamra Ii M, et al. Hepatoid adenocarcinoma
of the lung
: report of five cases and review of the literature. Mod Pathol 2014;27:535–42.
. Yasunami R, Hashimoto Z, Ogura T, et al. Primary lung
cancer producing alpha-fetoprotein: a case report. Cancer 1981;47:926–9.
. Yokoyama K, Morimoto H, Kaito S, et al. An autopsied case of alpha-fetoprotein (AFP) producing large cell carcinoma of the lung
(author's transl). Kyobu Geka 1981;34:609–12.
. Miyake M, Ito M, Taki T, et al. A case report of two patients with primary lung
cancer secreting AFP. Nihon Kyobu Geka Gakkai Zasshi 1986;34:914–9.
. Miyake M, Ito M, Mitsuoka A, et al. Alpha-fetoprotein and human chorionic gonadotropin-producing lung
cancer. Cancer 1987;59:227–32.
. Saka H, Sakai S, Kondo N, et al. Successful resection of alpha-fetoprotein-producing lung
cancer. Chest 1988;94:879–80.
. Okunaka T, Kato H, Konaka C, et al. Primary lung
cancer producing alpha-fetoprotein. Ann Thorac Surg 1992;53:151–2.
. Nasu M, Soma T, Fukushima H, et al. Hepatoid carcinoma of the lung
with production of alpha-fetoprotein and abnormal prothrombin: an autopsy case report. Mod Pathol 1997;10:1054–8.
. Arnould L, Drouot F, Fargeot P, et al. Hepatoid adenocarcinoma
of the lung
: report of a case of an unusual alpha-fetoprotein-producing lung
tumor. Am J Surg Pathol 1997;21:1113–8.
. Carlinfante G, Foschini MP, Pasquinelli G, et al. Hepatoid carcinoma of the lung
: a case report with immunohistochemical, ultrastructural and in-situ hybridization findings. Histopathology 2000;37:88–9.
. Hayashi Y, Takanashi Y, Ohsawa H, et al. Hepatoid adenocarcinoma
in the lung
. Genova S, Dikov D, Peshev Zh, et al. Hepatoid adenocarcinoma
of the lung
: a case report. Khirurgiia (Sofiia) 2003;59:45–7.
. Terracciano LM, Glatz K, Mhawech P, et al. Hepatoid adenocarcinoma
with liver metastasis mimicking hepatocellular carcinoma: an immunohistochemical and molecular study of eight cases. Am J Surg Pathol 2003;27:1302–12.
. Lino K, Ohta Y, Tamura M. A resected case of alpha-fetoprotein-producing hepatoid adenocarcinoma
of the lung
. Jpn J Lung
. Oshiro Y, Takada Y, Enomoto T, et al. A resected case of metachronous liver metastasis from lung
cancer producing alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist II (PIVKA-II). Hepatogastroenterology 2004;51:1144–7.
. Ivan M, Koss M, Chang CF. Hepatoid adenocarcinoma
of the lung
[abstract]. Chest 2007;132: Abstract 690.
. Kim L, Song JY, Jin X. Hepatoid adenocarcinoma
arising in the lung
: a case report. Basic Appl Pathol 2009;2:A47.
. Papatsimpas G, Kamposioras K, Goula K, et al. Hepatoid pancoast tumor. A case report and review of the literature. Lung
. Valentino F, Torchio M, Morbini P, et al. Synchronous presentation of hepatoid alpha-fetoprotein-producing lung
cancer and colorectal adenocarcinoma. Tumori 2012;98:130e–4e.
. Mokrim M, Belbaraka R, Allaoui M, et al. Hepatoid Adenocarcinoma
of the lung
: a case report and literature review. J Gastrointest Cancer 2012;43(Suppl 1):S125–7.
. Lin SF, Hsu WH, Chou TY. Primary pulmonary hepatoid carcinoma: report of a case and review of the literature. Kaohsiung J Med Sci 2013;29:512–6.
. Che YQ, Wang S, Luo Y, et al. Hepatoid adenocarcinoma
of the lung
: presenting mediastinal metastasis without transfer to the liver. Oncol Lett 2014;8:105–10.
. Shaib W, Sharma R, Mosunjac M, et al. Hepatoid adenocarcinoma
of the lung
: a case report and review of the literature. J Gastrointest Cancer 2014;45(Suppl 1):99–102.
. Gavrancic T, Park YH. A novel approach using sorafenib in alpha fetoprotein-producing hepatoid adenocarcinoma
of the lung
. J Natl Compr Canc Netw 2015;13:387–91.
. Motooka Y, Yoshimoto K, Semba T, et al. Pulmonary hepatoid adenocarcinoma
: report of a case. Surg Case Rep 2016;2:1.
. Sun JN, Zhang BL, Li LK, et al. Hepatoid adenocarcinoma
of the lung
without production of (-fetoprotein: a case report and review of the literature. Oncol Lett 2016;12:189–94.
. Qian GQ, Yin FY, Li GX, et al. Hepatoid adenocarcinoma
of the lung
. QJM 2016;109:619–20.
. Wang S, Li M, Chen H, et al. FDG PET/CT in hepatoid adenocarcinoma
of the lung
. Clin Nucl Med 2016;41:e340–1.
. Valle L, Thomas J, Kim C, et al. Hepatoid adenocarcinoma
of the lung
metastasizing to the tonsil. Mol Clin Oncol 2017;6:705–7.